The long-range goals of our research program are to investigate the mode of action, mechanism of cytotoxicity, and in vivo significance of natural killer cells (NK cells) both in the normal and in certain disease states such as neoplasia and Chediak-Higashi syndrome. NK cells are a recently discovered subpopulation of lymphoid cells that are present in most normal individuals. These cells have spontaneous cytolytic activity against a variety of tumor cells and some normal cells. Recent data on roles of NK cells in vivo suggest that these cells may provide the first line of defense against tumor growth and against infection by some microbial agents. Except for the requirement for NK cell-target cell recognition and binding, the molecular mechanism of action of NK cells is completely unknown. Our recent studies have demonstrated that the cytolytic activity of NK cells may be inhibited by certain hexose phosphates, while NK cell-target cell recognition and binding are unaffected. These results suggest that a soluble, hexose phosphate containing, lytic factor may be a mechanism by which target cells are destroyed by NK cells. The specific aims for the next three years are to: (1)\demonstrate a hexose phosphate receptor of target cells; (2)\isolate and characterize the soluble lytic factor; once these goals are accomplished, we will then (3)\investigate the role of the lysosome in NK cell-mediated target cell destruction; and (4)\examine NK cells of Pseudo-Hurlers and/or Chediak-Higashi patients to establish the basis for their low NK cell activity. It must be emphasized that these last two goals are obviously long-term investigations and are not within the scope of this present application. The finding of a major role for NK cells in natural resistance against bone marrow transplants has considerable implication for clinical bone marrow transplantation. If the molecular mechanism of NK cells is elucidated, then it may be possible to modify current procedures to ensure sustained depression of NK activity and thereby improve graft survival. In addition, if a major role for NK cells in resistance against tumor growth or other diseases is substantiated, then an understanding of the molecular mechanism of NK cells might lead to new or alternate strategies for immunoprevention or immunotherapy by stimulating NK cell activity. (LB)